Deep Sequencing of Relapse and Refractory Hodgkin Lymphoma Genomes: A Study of Tumor Biology and Evolution

霍奇金淋巴瘤（HL）占西方世界所有淋巴瘤的10%，并且仍然是一个恶性肿瘤。 严重的临床问题。复发性和难治性（R/R）HL是一种特别严重的未满足临床 因为大约25%的HL患者对标准治疗难治或复发， 接受治疗，R/R HL患者的总生存率约为50%。新的有针对性的治疗选择， 需要改进风险评估以改进这些患者的治疗选择。HL定义为： 一种罕见的恶性B细胞（霍奇金-里德-斯滕贝格，HRS细胞），占肿瘤的一小部分 微环境尽管下一代测序技术取得了许多进展，但对 以罕见细胞群为特征的癌症中的体细胞变异在技术上和分析上仍然存在 挑战性这些障碍导致使用高通量的研究数量有限 全基因组技术来表征新诊断的HL的基因组景观， 试图使用这些技术来解决R/R HL的基因组景观。在这里，我们解决这个问题， 通过提出三个问题来弥补不足：1）超深度全基因组测序，结合分析和 针对低VAF变异体优化的过滤策略鉴定了在R/R中驱动治疗抗性的体细胞变异体 HL？2)我们能否在一个新诊断和R/R HL的大队列中使用体细胞突变状态来识别基因 能预测治疗效果的东西吗3)在基因组和/或无细胞中能鉴定体细胞突变吗？ DNA描述了HRS细胞间的克隆异质性，无细胞DNA可以作为HL的生物标志物吗？ 诊断或复发？这项研究将具有广泛的影响力，因为：1）它将描述基因组 R/R HL的总体情况，并将确定可预测治疗反应不良的生物标志物; 2）它将 开始解决HL克隆结构、疾病结局和预后之间的关系; 3）它将 进一步将cfDNA定义为HL疾病监测的合适靶标 通过完成这项提案，Felicia Gomez博士将获得基因组学，生物信息学， 淋巴瘤生物学和癌症生物学。这项提议利用了最先进的基因组学 以及华盛顿大学医学院（WUSM）的癌症研究。WUSM是一个理想的位置， 完成本建议书中描述的实验和培训。戈麦斯博士是一位训练有素的学者， 准备开发一个研究计划，这将是创新的，并对多样性的需要作出反应， 生物医学劳动力。当戈麦斯博士过渡到独立，她将继续专注于癌症 基因组学，并将扩大她的研究，以解决体细胞和种系变异之间的相互作用 以及这种相互作用如何影响淋巴瘤和其他恶性肿瘤的发展和进展。

Hodgkin lymphoma (HL) accounts for ten percent of all lymphomas in the western world and remains a substantial clinical problem. Relapsed and refractory (R/R) HL presents a particularly critical unmet clinical need because approximately 25% of HL patients will be refractory to the standard of care or will relapse while receiving treatment, and the overall survival of R/R HL patients is ~50%. New targeted treatment options and improved risk assessment are needed to improve the therapeutic options for these patients. HL is defined by a rare malignant B cell (Hodgkin-Reed-Sternberg , HRS cells) that occupies a small fraction of the tumor microenvironment. Despite many advances in next generation sequencing technologies, the identification of somatic variants in cancers characterized by rare cell populations remains technically and analytically challenging. These obstacles have resulted in a limited number of studies that have used high throughput genome-wide technologies to characterize the genomic landscape of newly diagnosed HL, and far fewer have attempted to use these technologies to address the genomic landscape of R/R HL. Here, we address this shortfall by asking three questions: 1) Can ultra-deep genome-wide sequencing, paired with analysis and filtering strategies optimized for low VAF variants identify somatic variants driving treatment resistance in R/R HL? 2) Can we use somatic mutation status in a large cohort of newly diagnosed and R/R HL to identify genes that are predictive of response to therapy? 3) Can somatic mutations identified in genomic and/or cell free DNA describe clonal heterogeneity among HRS cells and can cell free DNA serve as biomarker of HL at diagnosis or relapse? This research will be broadly impactful because: 1) it will describe the genomic landscape of R/R HL and will identify biomarkers that are predictive of poor response to treatment; 2) it will begin to address the relationship between clonal architecture in HL, disease outcome, and prognosis; 3) it will further define cfDNA as a suitable target for HL disease monitoring By completing this proposal Dr. Felicia Gomez will gain advanced training in genomics, bioinformatics, lymphoma biology, and cancer biology in general. This proposal takes advantage of the cutting edge genomics and cancer research at Washington University School of Medicine (WUSM). WUSM is an ideal location to complete the experiments and training described in this proposal. Dr. Gomez is a well-trained scholar who is poised to develop a program of research that will be innovative and responsive to the need for diversity in the biomedical workforce. When Dr. Gomez transitions to independence she will continue to focus on cancer genomics and will broaden her research to address the interactions between somatic and germline variation and how this interaction affects the development and progression of lymphoma and other malignancies.